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The Thirsty Mind

The New Yorker reports on an article by a group of researchers from the Centre for Neural Circuits and Behaviour in the latest issue of the journal Nature Neuroscience. The group, which is led by Scott Waddell, studies rewards, motivation, and memory in the comparatively simple brain of the fruit fly.

Kent Berridge, a psychologist at the University of Michigan, has spent more than thirty years trying to understand the biology of rewards. How and where do pleasure and motivation—the impulse to eat a piece of chocolate cake, say, or to resist it—arise in the brain? Berridge divides the components of reward into “liking,” “wanting,” and “learning.” When human newborns, young orangutans, chimpanzees, monkeys, or even rats and mice taste something sweet, for instance, they all stick out their tongues just a little; this is liking. (When they taste something bitter, they all open their mouths in a remarkably similar gape.) They will try to get more of what they like; this is wanting. And, over the course of their lives, they will build up huge reservoirs of associations around whatever they like; this is learning.

In the science of reward, Berridge’s framework is both influential and controversial. “Our fundamental starting point,” he has written, “is that the temptation and pleasure of sweet, fatty, or salty foods arise actively within the brain, not just passively from physical properties of foods themselves. ‘Wanting’ and ‘liking’ reactions are actively generated by neural systems that paint the desire or pleasure onto the sensation—as a sort of gloss painted on the sight, smell or taste.”

In other words, the experience of reward is generated from within as well as from without. Presumably, there are dedicated places in the brain—Berridge calls them “hedonic hot spots”—where the gloss of pleasure is painted on, where a certain sheen and glimmer is cast over life’s rewards. But when scientists go hunting for these hot spots, using neural recordings and neuroimaging studies, they find them all over the place. So many brain areas light up in response to a sweet taste, a hit of intravenous cocaine, a jackpot win, or a subliminal glimpse of a smiley face that researchers can’t make much sense of what’s going on. They get lost in whole South Sea archipelagoes of hot spots. In one recent review of the literature, Berridge notes reward-related activity in the orbitofrontal cortex, the anterior cingulate, and the insula, as well as in deeper, subcortical structures, such as the nucleus accumbens, the ventral pallidum, the ventral tegmentum, the amygdala, and some of the dopamine pathways between them. Dopamine, a hormone secreted by certain neurons, is known to play a major role in pleasure and reward. But, amid all the neural activity generated by such broad categories of behavior as liking, wanting, and learning, it’s hard to figure out where it all starts in the mammalian brain.

The latest issue of the journal Nature Neuroscience includes an article by a group of researchers from the Centre for Neural Circuits and Behaviour, at Oxford. The group, which is led by Scott Waddell, studies rewards, motivation, and memory in the comparatively simple brain of the fruit fly. Drosophila melanogaster has been a tiny laboratory workhorse for more than a century, ever since it helped prove the theory of chromosomal inheritance. There are about a hundred thousand neurons in the fruit-fly brain, versus nearly ninety billion in the human brain. Its neural anatomy is very different from ours in the details—flies and mammals are separated by hundreds of millions of years of evolution. But it’s remarkably similar to ours in certain fundamental respects. By studying the anatomy of reward in the fly, Waddell and his colleagues hope to shed some light on human yearnings.

In their new paper, the researchers looked at the way flies respond to thirst, which hasn’t been studied much; most of the work in flies has focussed on hunger. For their experiments, Waddell and his team used a variation on the simple T-maze, which is a standard piece of apparatus in mind-of-the-fly laboratories. The maze confronts a fly with what is known as a choice point—a fork in the road. The fly stands before the vast mouths of two glass tubes. In one tube, the air is dry as dust. In the other, the air is damp. Which one will the fly enter?

If Waddell’s flies had spent the preceding day in a normal vial with the usual moist fly food (they are fond of molasses), most of them sniffed the air and walked into the dry tube. Flies don’t have noses, so they don’t literally sniff, but it’s known that they can detect humidity differences with their antennae. They have two specialized neurons devoted to that purpose in sensory hairs in their antennae’s third segment. One special neural channel, called nanchung, is tuned to the detection of dry air. Another channel is for moist air; that one is called water witch.

If, on the other hand, the flies had just spent six hours in a vial with nothing but dry paper lining the bottom, many of them would choose the damp, humid tube, even if they had never before encountered water in their lives (except for the moisture in their molasses, or the odd drop on the wall of their vial). And if the flies were really parched, if they had just spent the past fourteen hours on dry paper, nine out of ten of them chose the damp vial.

To speed things up a little, Waddell also tried keeping flies in a vial with a thick layer of Drierite underneath the dry paper. Drierite is a desiccant; people put it in safes, gun cabinets, and other closed-in spaces to keep the air dry. You can buy it at Walmart. After six hours, those were very thirsty flies. When they came to the choice point, they went running into the damp. In Berridge’s terms, the flies really wanted water. (The difference between “wanting” and “needing” gets a little confusing in Berridge’s scheme. Waddell explained it this way: “Wanting is seeking.”)

The question then was where in the fly’s brain the want signal was emerging. Whatever was going on in there, it likely offered a slightly simpler model of what goes on in our brains when we have a rewarding moment like that one—a drink of water after a day on Drierite. In previous work, Waddell and his colleagues had located a small cluster of neurons in the brains of the flies that seemed to be crucial to their dopamine-reward system. There are about a hundred and thirty of these neurons, and they feed dopamine to the horizontal lobes of a structure called the mushroom body, which is a part of the insect brain that is involved in learning and memory; the mushroom body is thought to be roughly equivalent to our hippocampus or cerebellum. When a fly tastes sugar, it is rewarded by a small subset of those hundred and thirty neurons, which deliver a hit of dopamine to the mushroom body. That particular subset of neurons appears to be specialized for sugar. They are the fly’s “Ah, sugar!” neurons; when they fire, that means “Hey, it’s sugar!,” and “Remember this!”

In the new paper, Waddell reports that there is a separate subset of neurons that hit the mushroom body with dopamine when a parched fly detects humidity—the “Ah, water!” neurons. They are hardwired in the fly—the fly is born with them, just as it’s born with nanchung and water witch and the associated hairs on its antennae. Those neurons go into action together when a fly smells water, even if it’s for the first time. That’s why the thirsty fly walks into the tube. This is wanting, in Berridge’s scheme.

“That’s one of the big surprises,” Waddell says. “It’s not just a general reward system that says, ‘This is good.’ There are separate reward systems for water and food.”

Waddell’s team found that yet another neural circuit goes into action when the fly remembers the taste of water, a separate hardwired circuit distinct from the circuitry of the “Ah, water!” neurons. This circuit helps the fly remember what it did at the choice point the last time it found the water. That’s learning, in Berridge’s scheme.

As for liking, the fly has no tongue to stick out, so it can’t lick its lips. But it does stick out its proboscis at a bead of sugar water, and there’s known to be a special neural circuit in the fly for that, too; it involves a special receptor called pickpocket 28. Probably there will turn out to be another separate circuit that makes the proboscis reach for water.

Scientists are beginning to dissect the reward system on an amazingly fine scale. As fly researchers like Waddell trace the wiring diagram of motivation, they are zooming in closer and closer, addressing smaller and smaller subpopulations of neurons. “Tiny groups, sometimes just two neurons,” he says. “So it really brings these mechanistic studies down to cellular resolution. That’s one of the reasons I use the fly.”

No one knows whether flies experience the same feelings that we do. But they offer a view of the mechanisms of liking, wanting, and learning at the level of nuts and bolts; and once you have the nuts and bolts, you can begin to tinker. “Playing with small numbers of neurons has profound effects,” Waddell says. “There are situations where we can generate flies that are seeking foods when they’re not hungry, or water when they’re not thirsty. So they’ve lost control, if you like.” The flies behave like people whose cravings have reached the point of obsession. “It’s not totally ridiculous to suggest,” Waddell says, that such studies may eventually help lead to the development of new drugs for what he calls, drily, “problematical humans.”

Tomorrow morning, a select group of leading neuroscientists will meet at the White House, where President Obama is expected to announce the next steps in his support for the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. It’s worth noting that the initiative, which is meant to advance our understanding of the human brain, will sponsor the study of other kinds of brains, too—those of flies, worms, jellyfish, hydra, and other seemingly less sophisticated creatures. Waddell’s paper is just one of about sixty thousand technical articles about the brain that have been published so far this year. Organisms like flies and worms are worth studying both because they are alien and because they aren’t. At the most basic level—food, water, sex—the nuts and bolts are remarkably alike. The more we learn about them, the better we will understand our human hungers and thirsts.